Alzheimer's disease is characterized by the aggregation of beta-amyloid (Abeta) protein in the brain, widespread neurodegeneration, and cognitive decline. Our work focuses on amelioration of Alzheimer's pathology and improving memory by modifying brain ganglioside distribution. We have shown that manipulating brain gangliosides in vivo are neuroprotective and reduce amyloid aggregation, and improve behavior in animal models. Although the manipulations differ, they all have in common the ability to increase the levels of GM1 in the brain. GM1 has been shown to be neuroprotective and enhance cognition in many different preparations. A published report with wild-type piglets demonstrates that dietary glycomacropeptide (GMP) improves spatial memory and increases levels of sialylated gangliosides in the brain. Although the study did not report levels of specifi gangliosides, the enhanced cognition suggests that GM1 is elevated. Our goal is to understand the role of gangliosides in Alzheimer's disease and how they relate to memory impairment, the earliest cognitive symptom of the disease. The objective of this application is to determine whether dietary administration of GMP is successful in alleviating features of Alzheimer's disease in the 5xFAD transgenic mouse model. The general hypothesis of the proposed research is that 5 months' administration of GMP will successfully reduce plaque formation and prevent neurodegeneration and memory impairments in adult mutant mice. In the proposed experiments, a GMP diet or control isolated soy protein (ISP) diet will be administered to 5xFAD and wild-type control mice. Spatial memory will be assessed, as well as control tests for anxiety and sensorimotor function. Post-mortem analyses will assess Alzheimer-related neuropathology and cell death, as well as lipid biochemistry. Successfully reducing amyloid burden, cell death, and memory impairment in the transgenic mice may provide insight into new treatment strategies for Alzheimer's disease-- treatments that could reduce or prevent dementia in Alzheimer patients. PUBLIC HEALTH RELEVANCE: The proposed experiments will test the effects of the food additive glycomacropeptide (GMP) on memory and Alzheimer-related neuropathology. The use of GMP represents not only a novel treatment strategy, but a novel therapeutic target for Alzheimer's disease. These experiments are consistent with the stated goals of National Institute on Aging and National Institute of Neurological Disorders and Stroke.